Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
  • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D309/30—Oxygen atoms, e.g. delta-lactones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

• the present invention relates to the area of chemotherapeutic agents and, more particularly, relates to certain substituted polyketides, and the use of said polyketides in treating tumors.
• anti-tumor agents which have been developed and found effective against cancer cells are, unfortunately, also toxic to normal cells. This toxicity manifests itself in weight loss, nausea, vomiting, hair loss, fatigue, itching, hallucinations, loss of appetite, etc., upon administration of the anti-tumor agent to a patient in need of cancer chemotherapy.
• conventionally used chemotherapeutic agents do not have the effectiveness desired or are not as broadly effective against different types of cancers as desired.
• chemotherapeutic agents which are not only more effective against all types of cancer, but which have a higher degree of selectivity for killing cancer cells with no or minimal effect on normal healthy cells.
• highly effective and selective anti-tumor agents in particular, against cancers of the colon, bladder, prostate, stomach, pancreas, breast, lung, liver, brain, testis, ovary, cervix, skin, vulva and small intestine are desired.
• anti-tumor activity against colon, breast, lung and prostate cancers as well as melanomas are particularly desired because of the lack of any particular effective therapy at the present time.
• (+)-Discodermolide is a novel polyketide natural product that was isolated from extracts of the marine sponge Discodermia dissoluta by researchers at the Harbor Branch Oceano- graphic Institution (HBOI) (Gunasekera SP, Gunasekera M, Longley RE, Schulte GK. Discodermolide: a new bioactive polyhydroxylated lactone from the marine sponge Discodermia dissoluta. [published erratum appears in J. Org. Chem. 1991 ;56:1346]. J. Org. Chem. 1990;55:4912-15.).
• HBOI Harbor Branch Oceano- graphic Institution
• Discodermolide lacks obvious structural resemblance to paclitaxel, yet it shares with paclitaxel (the active substance in the drug Taxol) the ability to stabilize microtubules. In mechanism-based assays, discodermolide is more effective than paclitaxel. Since paclitaxel has proven to be useful in treating some cancers, other compounds of the same mechanistic class may have utility against hyperproliferative disorders. Development of discodermolide or structurally related analogues is hindered by the lack of a reliable natural source of the compound or a feasible synthetic route. Naturally occurring discodermolide is scarce and harvesting the producing organism presents logistical problems. There is an ever-growing need for improved syntheses that enable production of multi-gram amounts of discodermolide and structurally related analogues.
• the present invention provides new anti-tumor agents which are effective against a variety of cancer cells. More particularly, the present invention relates to certain substituted polyketides which exhibit a higher degree of selectivity in killing cancer cells. In addition, the present invention provides pharmaceutical compositions useful in treating tumors comprising a therapeutically effective amount of a certain substituted polyketide. Moreover, the present invention provides a method of treating tumors comprising administering to a mammal afflicted therewith a therapeutically effective amount of a certain substituted polyketide alone or in combination with one or more other therapeutic agents.
• the essence of the instant invention is the discovery that certain substituted polyketides are useful in treating tumors.
• the instant invention provides new anti-tumor agents of formula I:
• A is H, (C ⁇ )alkyl, (C ⁇ )hydroxyalkyl, -(CH 2 )qCH(CO 2 R ⁇ )R ,
• B is -CH 2 CH(OR,)-, -CHzCHfOCf jR -, -OCH(R 4 )-, -N(R,)C(O)-,
• F is H, -C(0)N(R,) 2 , -C(O)NHCH 2 (CH 2 ) n N(CH 3 ) 2 , or
• R is H, (C ⁇ )alkyl, (C ⁇ )alkyl-Ar or Ar;
• Ar is an aromatic or heteroaromatic ring selected from independently, H, (C 1-6 )alkyl, OH, O(C 1-6 )alkyl, OCH 2 (CH 2 ) n OH, O(CH 2 ) n CO 2 H,
• R 4 is H or (C ⁇ )alkyl
• R 5 is (C ⁇ . 6 )alkyl, (C ⁇ )alkyl-Ar or Ar; m is 0 or 1 ; n is 1 or 2; and q is 0-6; with the proviso that when A is Ar or
• R a and R 5a is (C 1-6 )alkyl, then either:
• B cannot be -OCH(R 4 )- or -N(R 1 )C(O)-
• B when B is -CH 2 CH(OH)- or -OCH(R 4 )-, then C cannot be -OCH(R 4 )- 1 -N(R,)CH 2 - or -N(R,)C(0)-, and with the further proviso that the compound of formula I is not a compound of formulae
• Preferred compounds are those of formula la:
• B' is -CH 2 CH(OR v )-, -CH 2 CH(OC(O)R 1 )- I -OCH 2 -, -N(R, )C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
• B * is -CHzCHfORr)-, -CH 2 CH(OC(O)Rr)-, -OCH 2 -, -N(R v )C(O)-,
• F is H, -C(O)N(R r ) 2 , -C(O)NHCH 2 (CH 2 )nN(CH3) 2 or
• Rv is H, (C M )alkyl. (C ⁇ alkyl-Ar' or Ar";
• Ar is selected from
• R 2 ' and R 3 ' are, independently, H, (C ⁇ )alkyl, OH, O(C ⁇ . 3 )alkyl, OCH 2 (CH 2 ) n OH,
• R ff is (d ⁇ alkyl, (d ⁇ alkyl-Ar" or Ar'; m is 0 or 1 ; and n is 1 or 2; and wherein the foregoing provisos apply; or an acid or base addition salt thereof, where possible.
• More preferred compounds are those of formula lb:
• B" is -CH 2 CH(OR r )-, -CH 2 CH(OC(O)R r )-, -OCH 2 -, -N(R r )C(0)-,
• R 2 " and R 3 " are, independently, H, (C ⁇ )alkyl, OH, OCH 3> OCH 2 CH 2 OH, OCH 2 C0 2 H, OCH 2 (CH 2 ) n N(CH 3 ) 2 , OCH 2 (CH 2 ) n -4-morpholino, F, CI, Br or CF 3 ;
• R » is H or CH 3 ;
• R 5 - is (C ⁇ )alkyl, -CH 2 -Ar" or Ar" m is 0 or 1 ; and n is 1 or 2; and wherein the foregoing provisos apply; or an acid or base addition salt thereof, where possible
• B"' is -CH 2 CH(OR )-, -CH 2 CH(OC(O)R r )-, -OCH 2 -, -N(R r )C(O)-, -CH 2 C(O)- or -CH 2 CH 2 -;
• R r is H, -CH 3 , CH 2 -Ar'" or Ar"';
• Ar'" is selected from
• R 2 '" and R 3 '" are, independently, H, (C 1-4 )alkyl, OH, OCH 3 , OCH 2 CO 2 H, OCH 2 (CH 2 ) n N(CH 3 ) 2 , OCH 2 (CH 2 ) n -4-morpholino, F, CI, Br or CF 3 ;
• R 4" is as defined above;
• Rr is (C 1- ⁇ )alkyl, -CH 2 -Ar'" or Ar'"; m is 0 or 1 ; and n is 1 or 2; and wherein the foregoing provisos apply; or an acid or base addition salt thereof, where possible.
• the instant invention provides pharmaceutical compositions useful in treating tumors comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable acid or base addition salt thereof, where possible, preferably a compound of formula la above, or a pharmaceutically acceptable acid or base addition salt thereof, where possible, more preferably a compound of formula lb above, or a pharmaceutically acceptable acid or base salt thereof, where possible, and even more preferably a compound of formula Ic above, or a pharmaceutically acceptable acid or base addition salt thereof, where possible.
• the instant invention provides a method for treating tumors comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable acid or base addition salt thereof, where possible, preferably a compound of formula la above, or a pharmaceutically acceptable acid or base addition salt thereof, where possible, more preferably a compound of formula lb above, or a pharmaceutically acceptable acid or base addition salt thereof, where possible, and even more preferably a compound of formula Ic above, or a pharmaceutically acceptable acid or base addition salt thereof, where possible, alone or in combination with one or more other therapeutic agents.
• the alkyl groups containing 1 to 6 carbon atoms are either straight or branched chain or cycloalkane, of which examples include isopropyl, isobutyl, f-butyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbuty, 1,1 ,2,2-tetramethylethyl, cyclopentyl and cyclohexyl.
• the acid addition salts of the compounds of formula I may be those of pharmaceutically acceptable organic or inorganic acids.
• the preferred acid addition salts are those of hydrochloric and methanesulfonic acid, salts of sulfuric, phosphoric, citric, fumaric, maleic, benzoic, benzenesulfonic, succinic, tartaric, lactic and acetic acid may also be utilized.
• the base addition salts of the compounds of formula I may be those of pharmaceutically acceptable organic or inorganic bases.
• Preferred base addition salts are those derived from pharmaceutically acceptable inorganic bases, more preferably ammonium hydroxide or an alkali or alkaline earth metal hydroxide, e.g, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide and manganese hydroxide.
• the substituted polyketides of formula I may be prepared as depicted below.
• the asterisk designation indicates that those groups are protected with acid labile protecting groups (for example TBS). All acid labile protecting groups covered by the asterisk are removed in the final step (HCI).
• Step A involves the olefination of an aldehyde of formula 2 with a phosphonate of formula 1 to obtain an olefin of formula 3.
• the olefination is conducted in the presence of: 1 ) a strong base, preferably a potassium salt such as potassium hexamethyldisilazide; 2) a crown ether such 18-crown-6; and 3) an inert organic solvent, preferably a hydrocarbon such as toluene, at a temperature of between -78°C and 25°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a strong base preferably a potassium salt such as potassium hexamethyldisilazide
• a crown ether such 18-crown-6
• an inert organic solvent preferably a hydrocarbon such as toluene
• Step B concerns the carbamoylation of the olefin of formula 3 with a an isocyanate either of formula F*NCO or CI 3 C(O)NCO to give a carbamate of formula 4.
• the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• a protic organic solvent preferably an alcohol such as methanol
• a base for example, a carbonate such as potassium carbonate
• Step C concerns the reduction of carbamate 4 to a hydroxy compound of formula 5.
• the reduction is conducted in the presence of: 1 ) a hydride, preferably a borane such as catechol borane; 2) a catalyst, preferably a chiral alkyl boron catalyst such as (F?)-tetrahydro- 1-butyl-3,3-diphenyl-1 H, 3H-pyrrolo[1 ,2-c][1 ,3,2]oxazaborole; and 3) an inert organic solvent, preferably a hydrocarbon such as toluene, at a temperature of between -78°C and 25°C, preferably at -20°C, for a period of between 10 hours and 7 days, preferably for 1-4 days.
• a hydride preferably a borane such as catechol borane
• a catalyst preferably a chiral alkyl boron catalyst such as (F?)-tetrahydro- 1-butyl-3,3-dip
• Step D concerns the hydrolysis of hydroxy compound 5 to a substituted polyketide of formula 6.
• the hydrolysis reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20 C C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents, preferably a mixture of an ali
• Step C concerns the hydrolysis of carbamate 4 to a different substituted polyketide of formula 7.
• the hydrolysis reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents, preferably a mixture of an
• Step A involves the addition of a ketone of formula EtO 2 CCH 2 (CH 2 )nC(O)CH 3 where n is as defined above with an aldehyde of formula 1 to obtain a hydroxyketone of formula 2.
• the addition requires between 1 and 20 equivalents of the ketone EtO 2 CCH 2 (CH 2 )nC(O)CH 3 relative to aldehyde 1, preferably between 5 and 15 equivalents of the ketone EtO 2 CCH 2 (CH 2 )nC(0)CH 3 relative to aldehyde 1.
• the coupling is conducted in the presence of: 1 ) a dialkylboron halide or triflate, preferably a chiral boron chloride or triflate, more preferably ⁇ -chlorodiisopinocampheylborane; 2) a base, preferably an amine, more preferably triethylamine; and 3) a polar organic solvent, preferably an ether, more preferably diethyl ether, at a temperature of between -100°C and 20°C, preferably between -78°C and -20°C, for a period of between 2 and 72 hours, preferably for 16 hours.
• a dialkylboron halide or triflate preferably a chiral boron chloride or triflate, more preferably ⁇ -chlorodiisopinocampheylborane
• 2) a base preferably an amine, more preferably triethylamine
• 3) a polar organic solvent preferably an ether,
• Step B concerns the reduction of the ketone group common to hydroxyketones of formula 2, to obtain a 1 ,3-diol compound of formula 3.
• the reduction is conducted in the presence of: 1 ) a ketone reducing agent, preferably a borohydride such as tetramethylammonium triacetoxyborohydride; 2) a polar organic solvent, preferably acetonitrile; and 3) a protic solvent, preferably a carboxylic acid, such as acetic acid, at a temperature of between -78°C and 20°C, preferably between -40°C and -10°C, for a period of between 2 and 72 hours, preferably for 16 hours.
• a ketone reducing agent preferably a borohydride such as tetramethylammonium triacetoxyborohydride
• 2) a polar organic solvent preferably acetonitrile
• 3) a protic solvent preferably a carboxylic acid, such as acetic acid, at
• Step C concerns the hydrolysis and cyclization of the 1 ,3-diol compound 3 to a substituted polyketide of formula 4.
• the hydrolysis reaction is conducted in the presence of: 1 ) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25 C C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of
• Step A involves the acylation of an alcohol of formula 1 with an acylating compound, preferably a chloroformate such as 4-nitrophenyl chloroformate, to obtain a carbonate of formula 2.
• the acylation is conducted in the presence of: 1) a weak base, preferably an amine, more preferably triethylamine; 2) an acylation catalyst, preferably a pyridine such a 4-dimethylaminopyridine; and 3) a polar organic solvent, such as methylene chloride or ethyl acetate, at a temperature of between -10°C and 50°C, preferably between -5°C and 20°C, for a period of between 10 minutes and 24 hours, preferably for 2 hours.
• a weak base preferably an amine, more preferably triethylamine
• an acylation catalyst preferably a pyridine such a 4-dimethylaminopyridine
• 3) a polar organic solvent such as methylene chloride or ethyl
• Step B concerns the carbamoylation of the carbonate of formula 2, to obtain a carbamate compound of formula 3.
• the carbamoylation is conducted in the presence of: 1) an amine of formula A * NHR 1 * , where A * and Ri * are as defined above; and 2) a polar organic solvent, such as methylene chloride or ethyl acetate, at a temperature of between -78°C and 50°C, preferably between -20°C and 25°C, for a period of between 2 and 72 hours, preferably for 16 hours.
• a polar organic solvent such as methylene chloride or ethyl acetate
• Step C concerns the carbamoylation of the carbamate of formula 3 with a an isocyanate either of formula F * NCO or CI 3 C(O)NCO to give a bis(carbamate) of formula 4.
• F * NCO the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• a protic organic solvent preferably an alcohol such as methanol
• a base for example, a carbonate such as potassium carbonate
• Step D concerns the hydrolysis of the bis(carbamate) of formula 4 to a substituted polyketide of formula 5.
• the hydrolysis reaction is conducted in the presence of: 1 ) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents,
• Step A involves the carbamoylation of the diol of formula 1_, to obtain a carbamate compound of formula 2.
• the carbamoylation is conducted in the presence of: 1 ) an isocyanate of formula A * NCO, where A* is as described above; 2) a polar organic solvent, such as methylene chloride or ethyl acetate; and 3) a Lewis acid catalyst such as dibutyltin diacetate or a weak base such as triethylamine, at a temperature of between -78°C and 60°C, preferably between 0°C and 40°C, for a period of between 2 and 72 hours, preferably for 16 hours.
• Step B concerns the carbamoylation of the carbamate of formula 2 with a an isocyanate either of formula F*NCO or CI 3 C(O)NCO to give a bis(carbamate) of formula 3.
• the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride, at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• a protic organic solvent preferably an alcohol such as methanol
• a base for example, a carbonate such as potassium carbonate
• Step C concerns the hydrolysis of the bis(carbamate) of formula 3 to a substituted polyketide of formula 4.
• the hydrolysis reaction is conducted in the presence of: 1 ) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents,
• Step A involves the alkylation of the alcohol of formula 1 to obtain an ether compound of formula 2.
• the alkylation is conducted in the presence of: 1) an alcohol of formula A * OH, where A * is as described above; 2) a coupling reagent such as diethyl azodicarboxylate; 3) a phosphine such as triphenylphosphine; and 4) a polar organic solvent, such as tetrahydrofuran, at a temperature of between -78°C and 60°C, preferably between -20°C and 40°C, for a period of between 2 and 72 hours, preferably for 16 hours.
• a coupling reagent such as diethyl azodicarboxylate
• 3) a phosphine such as triphenylphosphine
• a polar organic solvent such as tetrahydrofuran
• Step B concerns the hydrolysis of an ether of formula 2 to a substituted polyketide of formula 3.
• the hydrolysis reaction is conducted in the presence of: 1 ) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents, preferably a mixture
• Step A involves the olefination of an aldehyde of formula 2 with a phosphonate of formula 1 to obtain an olefin of formula 3.
• the olefination is conducted in the presence of: 1) a strong base, preferably a potassium salt such as potassium hexamethyldisilazide; 2) a crown ether such 18-crown-6; and 3) an inert organic solvent, preferably a hydrocarbon such as toluene, at a temperature of between -78°C and 25°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a strong base preferably a potassium salt such as potassium hexamethyldisilazide
• a crown ether such 18-crown-6
• an inert organic solvent preferably a hydrocarbon such as toluene
• Step B concerns the carbamoylation of the olefin of formula 3 with a an isocyanate either of formula F * NCO or CI 3 C(O)NCO to give a carbamate of formula 4.
• the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• a protic organic solvent preferably an alcohol such as methanol
• a base for example, a carbonate such as potassium carbonate
• Step C concerns the hydrolysis of the carbamate of formula 4 to a substituted polyketide of formula 5.
• the hydrolysis reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• Scheme 7
• Step A involves the olefination of an aldehyde of formula 2 with a phosphonium salt of formula 1 to obtain an olefin of formula 3.
• the olefination is conducted in the presence of: 1 ) a strong base, preferably an alkali metal salt such as potassium hexamethyldisilazide or butyllithium; and 2) an inert organic solvent, preferably a hydrocarbon such as toluene, or an ether such as tetrahydrofuran, at a temperature of between -78°C and 25°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a strong base preferably an alkali metal salt such as potassium hexamethyldisilazide or butyllithium
• an inert organic solvent preferably a hydrocarbon such as toluene, or an ether such as tetrahydrofuran
• Step B concerns the carbamoylation of the olefin of formula 3 with a an isocyanate either of formula F * NCO or CI 3 C(O)NCO to give a carbamate of formula 4.
• the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• a protic organic solvent preferably an alcohol such as methanol
• a base for example, a carbonate such as potassium carbonate
• Step C concerns the hydrolysis of the carbamate of formula 4 to a substituted polyketide of formula 5.
• the hydrolysis reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents, preferably a mixture of
• Step A involves the oxidation of an alcohol of formula I to obtain an aldehyde of formula 2.
• the oxidation is conducted in the presence of: 1) an oxidizing reagent, preferably a mild oxidizing reagent such as the combinations of oxalyl chloride, DMSO and triethylamine; sulfur trioxide-pyridine complex, DMSO and triethylamine; and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical and diacetoxyiodo- benzene; and 2) an inert organic solvent, preferably a polar organic solvent such as methylene chloride, at a temperature of between -78°C and 40°C, preferably from -20°C to 25°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• an oxidizing reagent preferably a mild oxidizing reagent such as the combinations of oxalyl chloride, DMSO and triethylamine; sulfur
• Step B involves the reductive amination of an aldehyde of formula 2 to obtain an amine of formula 3.
• the reductive amination is conducted in the presence of: 1) an amine of formula R NH 2 where R ⁇ * is as defined above; 2) a reducing agent, preferably a hydride, more preferably a borohydride salt such as sodium borohydride; and 3) a polar organic solvent, preferably a protic organic solvent such as ethanol, at a temperature of between 0°C and 40°C, preferably from 5°C to 25°C, for a period of between 10 minutes and 48 hours, preferably for 16 hours.
• Step C involves the acylation of an amine of formula 3 with an acylating compound, preferably a chloroformate such as 4-nitrophenyl chloroformate, to obtain a carbonate of formula 4.
• the acylation is conducted in the presence of: 1 ) a weak base, preferably an amine, more preferably triethylamine; 2) an acylation catalyst, preferably a pyridine such a 4-dimethylaminopyridine; and 3) a polar organic solvent, such as methylene chloride or ethyl acetate, at a temperature of between -10°C and 50°C, preferably between -5°C and 20°C, for a period of between 10 minutes and 24 hours, preferably for 2 hours.
• a weak base preferably an amine, more preferably triethylamine
• an acylation catalyst preferably a pyridine such a 4-dimethylaminopyridine
• a polar organic solvent such as methylene chloride or ethy
• Step D concerns the amidation of the carbamate of formula 4, to obtain a urea compound of formula 5.
• the carbamoylation is conducted in the presence of: 1) an amine of formula A * NHR , where A * and R, * are as defined above; and 2) a polar organic solvent, such as methylene chloride or ethyl acetate, at a temperature of between -78°C and 50°C, preferably between -20°C and 25°C, for a period of between 2 and 72 hours, preferably for 16 hours.
• a polar organic solvent such as methylene chloride or ethyl acetate
• Step E concerns the carbamoylation of the urea of formula 5 with a an isocyanate either of formula F * NCO or CI 3 C(O)NCO to give a carbamate of formula 6.
• F * NCO the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride, at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• Step F concerns the hydrolysis of carbamate of formula 6 to a substituted polyketide of formula 7.
• the hydrolysis reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents, preferably a mixture of an
• Step A involves the acylation of an alcohol of formula 1 to obtain an ester of formula 2.
• the acylation is conducted in the presence of: 1 ) a carboxylic acid of formula A * CH 2 CO 2 H where A * is as defined above; 2) a carboxylic acid coupling reagent, preferably a diimide such as 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, and a suitable activating agent common to diimide coupling reactions, preferably a substituted pyridine such a 4-dimethylaminopyridine; and 3) an inert organic solvent, preferably a chlorinated alkane such as methylene chloride, at a temperature of between -78°C and 25°C for a period of between 1 and 24 hours.
• a carboxylic acid of formula A * CH 2 CO 2 H where A * is as defined above 2
• a carboxylic acid coupling reagent preferably a diimide such as 1-(
• Step B concerns the carbamoylation of the ester of formula 2 with a an isocyanate either of formula F*NCO or CI 3 C(O)NCO to give a carbamate of formula 3.
• the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• a protic organic solvent preferably an alcohol such as methanol
• a base for example, a carbonate such as potassium carbonate
• Step C concerns the hydrolysis of carbamate of formula 3 to a substituted polyketide of formula 4.
• the hydrolysis reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours
• Step A involves the acylation of an amine of formula 1 to obtain an amide of formula 2.
• the acylation is conducted in the presence of: 1 ) a carboxylic acid of formula A * CH 2 CO 2 H where A * is as defined above; 2) a carboxylic acid coupling reagent, preferably a diimide such as 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, and a suitable activating agent common to diimide coupling reactions, such as 1 -hydroxybenzotriazole; and 3) a polar organic solvent, preferably a low molecular weight amide such as DMF, at a temperature of between 0°C and 40°C, preferably at 25°C, for a period of between 1 and 24 hours.
• a carboxylic acid of formula A * CH 2 CO 2 H where A * is as defined above 2) a carboxylic acid coupling reagent, preferably a diimide such as 1-(3-dimethyl
• Step B concerns the carbamoylation of the amide of formula 2 with a an isocyanate either of formula F * NCO or CI 3 C(O)NCO to give a carbamate of formula 3.
• the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride, at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• Step C concerns the hydrolysis of the carbamate of formula 3 to a substituted polyketide of formula 4.
• the hydrolysis reaction is conducted in the presence of: 1 ) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents, preferably a
• Step A involves the alkylation of an alcohol of formula to obtain an ether of formula 2.
• the alkylation is conducted in the presence of: 1) an alkyl iodide of formula A * CH 2 CH 2 I where A * is as defined above; 2) a strong base, such as sodium hydride, LDA or silver oxide; and 3) a polar organic solvent, such as DMF or tetrahrdrofuran, at a temperature of between -78°C and 40°C, preferably from -20°C to 25°C, for a period of between 1 and 24 hours.
• a strong base such as sodium hydride, LDA or silver oxide
• a polar organic solvent such as DMF or tetrahrdrofuran
• Step B concerns the carbamoylation of the ether of formula 2 with a an isocyanate either of formula F*NCO or CI 3 C(O)NCO to give a carbamate of formula 3.
• the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride, at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• a protic organic solvent preferably an alcohol such as methanol
• a base for example, a carbonate such as potassium carbonate
• Step C concerns the hydrolysis of the carbamate of formula 3 to a substituted polyketide of formula 4.
• the hydrolysis reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents, preferably a mixture of an
• Step A involves the reductive amination with an amine of formula 1 to obtain an amine of formula 2.
• the reductive amination is conducted in the presence of: 1) an aldehyde of formula A * CHO where A * is as defined above; 2) a reducing agent, preferably a hydride, more preferably a borohydride salt such as sodium borohydride; and 3) a polar organic solvent, preferably a protic organic solvent such as ethanol, at a temperature of between 0°C and 40°C, preferably from 5°C to 25°C, for a period of between 10 minutes and 48 hours, preferably for 16 hours.
• Step B concerns the carbamoylation of the amine of formula 2 with a an isocyanate either of formula F * NCO or CI 3 C(O)NCO to give a carbamate of formula 3.
• the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride, at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• a protic organic solvent preferably an alcohol such as methanol
• a base for example, a carbonate such as potassium carbonate
• Step C concerns the hydrolysis of the carbamate of formula 3 to a substituted polyketide of formula 4.
• the hydrolysis reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents, preferably a mixture of
• Step A involves the oxidation an aldehyde of formula ⁇ _ to obtain a carboxylic acid of formula 2.
• the oxidation is conducted in the presence of: 1) an oxidizing agent such as sodium chlorite; 2) a phosphate salt, preferably sodium dihydrogenphosphate; 3) a protic organic solvent, preferably an alcohol such as t-butanol; and 4) an alkene, preferably 2-methylpropene, at a temperature of between 0°C and 40°C, preferably at 25°C, for a period of between 10 minutes and 8 hours, preferably for 1 hour.
• an oxidizing agent such as sodium chlorite
• a phosphate salt preferably sodium dihydrogenphosphate
• 3) a protic organic solvent preferably an alcohol such as t-butanol
• an alkene preferably 2-methylpropene
• Step B involves the acylation of a carboxylic acid of formula 2 to obtain an amide of formula 3.
• the acylation is conducted in the presence of: 1) an amine of formula A * CH 2 CH 2 NHR ⁇ * where A* and Ri * are as defined above; 2) a carboxylic acid coupling reagent, preferably a diimide such as 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and a suitable activating agent common to diimide coupling reactions, such as 1 -hydroxybenzotriazole; and 3) a polar organic solvent, preferably a low molecular weight amide such as DMF, at a temperature of between 0°C and 40°C, preferably at 25°C, for a period of between 1 and 24 hours.
• a carboxylic acid coupling reagent preferably a diimide such as 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimi
• Step C concerns the carbamoylation of the amide of formula 3 with a an isocyanate either of formula F * NCO or CI 3 C(0)NCO to give a carbamate of formula 4.
• F * NCO the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably between 0°C and 50 C C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride, at a temperature of between -20°C and 100°C, preferably between 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• Step D concerns the hydrolysis of a carbamate of formula 4 to a substituted polyketide of formula 5.
• the hydrolysis reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents, preferably a mixture
• Step A involves the palladium-mediated coupling of an alkyl iodide of formula 1 and a vinyl iodide of formula 2 to obtain an alkene of formula 3.
• the palladium-mediated coupling is conducted in the presence of: 1) a hindered organo- metallic reagent, preferably a hindered organolithium reagent such as t-butyllithium; 2) either a zinc halide such as zinc chloride or a hindered boron reagent such as 9-methoxy-9- borabicyclo[3.3.1]nonane; 3) a palladium reagent such as tetrakis(triphenylphosphine)- palladium(O) or [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(ll); and 4) a polar organic solvent, preferably an ether such as diethyl ether, at a temperature of between -
• Step B involves the oxidative hydrolysis of an alkene of formula 3 to a diol of formula 4.
• the oxidative hydrolysis is conducted in the presence of 1) an oxidant, preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone; 2) water; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 1 hour and 72 hours, preferably for 1 hour.
• an oxidant preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone
• water preferably a polar organic solvent
• a polar organic solvent preferably a halogenated hydrocarbon such as methylene chloride
• Step A involves the olefination of an aldehyde of formula 2 with a phosphonium salt of formula 1 to obtain an alkene of formula 3.
• the olefination is conducted in the presence of: 1) a strong base, preferably an alkali metal salt such as potassium hexamethyldisilazide or butyllithium; and 2) an inert organic solvent, preferably a hydrocarbon such as toluene, or an ether such as tetrahydrofuran, at a temperature of between -78°C and 25°C, preferably at 0 C C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a strong base preferably an alkali metal salt such as potassium hexamethyldisilazide or butyllithium
• an inert organic solvent preferably a hydrocarbon such as toluene, or an ether such as tetrahydrofuran
• Step B involves the oxidative hydrolysis of an alkene of formula 3 to a diol of formula 4.
• the oxidative hydrolysis is conducted in the presence of 1 ) an oxidant, preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone; 2) water; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 1 hour and 72 hours, preferably for 1 hour.
• Step A involves the olefination of an aldehyde of formula ⁇ with a phosphonium salt of formula 2 to obtain an alkene of formula 3.
• the olefination is conducted in the presence of: 1 ) a strong base, preferably an alkali metal salt such as potassium hexamethyldisilazide or butyllithium; and 2) an inert organic solvent, preferably a hydrocarbon such as toluene, or an ether such as tetrahydrofuran, at a temperature of between -78°C and 25°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a strong base preferably an alkali metal salt such as potassium hexamethyldisilazide or butyllithium
• an inert organic solvent preferably a hydrocarbon such as toluene, or an ether such as tetrahydrofuran
• Step B involves the oxidative hydrolysis of an alkene of formula 3 to a diol of formula 4.
• the oxidative hydrolysis is conducted in the presence of 1 ) an oxidant, preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone; 2) water; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 1 hour and 72 hours, preferably for 1 hour.
• Step A involves the olefination of an aldehyde of formula 1 with a phosphonate of formula 2 to obtain an olefin of formula 3.
• the olefination is conducted in the presence of: 1) a strong base, preferably a potassium salt such as potassium hexamethyldisilazide; 2) a crown ether such 18-crown-6; and 3) an inert organic solvent, preferably a hydrocarbon such as toluene, at a temperature of between -78°C and 25°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a strong base preferably a potassium salt such as potassium hexamethyldisilazide
• a crown ether such 18-crown-6
• an inert organic solvent preferably a hydrocarbon such as toluene
• Step B involves the oxidative hydrolysis of an alkene of formula 3 to a diol of formula 4.
• the oxidative hydrolysis is conducted in the presence of: 1 ) an oxidant, preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone; 2) water; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 1 hour and 72 hours, preferably for 1 hour.
• Step A involves the olefination of an aldehyde of formula I with a phosphonate of formula 2 to obtain an olefin of formula 3.
• the olefination is conducted in the presence of: 1) a strong base, preferably a potassium salt such as potassium hexamethyldisilazide; 2) a crown ether such 18-crown-6; and 3) an inert organic solvent, preferably a hydrocarbon such as toluene, at a temperature of between -78°C and 25°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a strong base preferably a potassium salt such as potassium hexamethyldisilazide
• a crown ether such 18-crown-6
• an inert organic solvent preferably a hydrocarbon such as toluene
• Step B involves the oxidative hydrolysis of an alkene of formula 3 to a diol of formula 4.
• the oxidative hydrolysis is conducted in the presence of: 1 ) an oxidant, preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone; 2) water; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 1 hour and 72 hours, preferably for 1 hour.
• Step A involves the addition of a butene group to an aldehyde of formula 1 to obtain an alcohol of formula 2.
• a crotylboron reagent preferably a chiral crotylboron reagent, more preferably a Z-crotylboronate derived from diisopropyl tartrate
• an optional drying reagent such as molecular sieves
• an inert organic solvent preferably a hydrocarbon such as toluene, at a temperature of between -100°C and 5°C, preferably at -78°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• Step B involves the alkylation of an alcohol of formula 2 to obtain an alcohol of formula 3.
• the alkylation is conducted in the presence of: 1) a reactive benzylating reagent, preferably a reactive para-methoxybenzylating reagent such as p-methoxybenzyl-2,2,2- trichloroacetimidate; 2) a proton source, preferably a sulfonic acid such as pyridinium p-toluenesulfonate; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -78°C and 25°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a reactive benzylating reagent preferably a reactive para-methoxybenzylating reagent such as p-methoxybenzyl-2,2,2- trichloroacetimidate
• Step C involves the two stage oxidative cleavage of an alcohol of formula 3 to obtain an aldehyde of formula 4.
• the first stage of the oxidative cleavage is conducted in the presence of: 1) a dihydroxylating reagent, preferably an osmium reagent such as osmium tetroxide; 2) a cooxidant such as N-morpholine-N-oxide; and 3) a mixture of aprotic polar and protic solvents such as a mixture of acetone, water, and t-butanol, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a dihydroxylating reagent preferably an osmium reagent such as osmium tetroxide
• a cooxidant such as N-morpholine-N-oxide
• the second stage of the oxidative cleavage is conducted in the presence of: 1 ) a periodate salt such as sodium periodate; and 2) a mixture of aprotic polar and protic solvents such as a mixture of tetrahydrofuran and water, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a periodate salt such as sodium periodate
• a mixture of aprotic polar and protic solvents such as a mixture of tetrahydrofuran and water
• Step D involves the addition of a butene group to an aldehyde of formula 4 to obtain an alcohol of formula 5.
• the addition is conducted in the presence of: 1 ) a crotyl addition reagent, preferably a crotyltin reagent such as crotyltributyltin; 2) a Lewis acid such as borontrifluoride etherate; and 3) an inert organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -100°C and 5°C, preferably at -78°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• a crotyl addition reagent preferably a crotyltin reagent such as crotyltributyltin
• a Lewis acid such as borontrifluoride etherate
• an inert organic solvent preferably a halogenated hydrocarbon such as methylene chlor
• Step E involves the silylation of an alcohol of formula 5 to obtain a silyl ether of formula 6.
• the silylation is conducted in the presence of: 1) a silylating reagent, preferably a t-butyldimethylsilylating reagent such as t-butyldimethylsilyltriflate; 2) a weak base, preferably a nitrogen-containing base, more preferably a pyridine base such as 2,6-lutidine; and 3) an inert organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -100°C and 5°C, preferably at -20°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• Scheme 21 a silylating reagent, preferably a t-butyldimethylsilylating reagent such as t-butyldimethylsilyltriflate
• a weak base preferably a nitrogen-containing
• Step A involves the two stage oxidative cleavage of an alkene of formula 1 to obtain an aldehyde of formula 2.
• the first stage of the oxidative cleavage is conducted in the presence of: 1) a dihydroxylating reagent, preferably an osmium reagent such as osmium tetroxide; 2) a cooxidant such as N-morpholine-N-oxide; and 3) a mixture of aprotic polar and protic solvents such as a mixture of acetone, water, and t-butanol, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a dihydroxylating reagent preferably an osmium reagent such as osmium tetroxide
• a cooxidant such as N-morpholine-N-oxide
• 3) a mixture of aprotic polar and protic solvents such as a mixture of acetone, water, and t-butanol
• the second stage of the oxidative cleavage is conducted in the presence of: 1 ) a periodate salt such as sodium periodate; 2) a mixture of aprotic polar and protic solvents such as a mixture of tetrahydrofuran and water, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• Step B involves the reduction of an aldehyde of formula 2 to obtain an alcohol of formula 3.
• the reduction is conducted in the presence of: 1) a hydride reducing agent, preferably an aluminum hydride such as lithium aluminum hydride or diisobutylaluminum hydride, or a borohydride such as sodium borohydride; and 2) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -100°C and 40°C, preferably from -20°C to 25°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• a hydride reducing agent preferably an aluminum hydride such as lithium aluminum hydride or diisobutylaluminum hydride, or a borohydride such as sodium borohydride
• a polar organic solvent preferably an ether such as tetrahydrofuran
• Step C involves the iodination of an alcohol of formula 3 to obtain an iodide of formula 4.
• the iodination is conducted in the presence of: 1 ) an iodinating reagent such l 2 ; 2) a phosphorus-containing compound such as triphenylphoshine; 3) a weak base, preferably a weak nitrogen-containing base such as imidazole; and 4) a polar organic solvent, preferably an ester such as ethyl acetate, at a temperature of between -10°C and 40°C, preferably at 25°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• an iodinating reagent such l 2 ; 2) a phosphorus-containing compound such as triphenylphoshine; 3) a weak base, preferably a weak nitrogen-containing base such as imidazole; and 4) a polar organic solvent, preferably an ester such as ethyl acetate,
• Step D involves the two stage hydroxylation of an alkene of formula 1 to obtain an alcohol of formula 5.
• the first stage of the hydroxylation is conducted in the presence of: 1) a borane such as 9-borabicyclo[3.3.1]nonane; and 2) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -10°C and 40°C, preferably at 0°C, for a period of between 1 hour and 48 hours, preferably for 24 hours.
• a borane such as 9-borabicyclo[3.3.1]nonane
• a polar organic solvent preferably an ether such as tetrahydrofuran
• the second stage of the hydroxylation is conducted in the presence of: 1) an oxidant, preferably a peroxide such as hydrogen peroxide; 2) a strong alkali base, preferably a hydroxide base such as sodium hydroxide; and 3) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -10°C and 40°C, preferably at 0°C, for a period of between 10 minutes and 8 hours, preferably for 1 hour.
• an oxidant preferably a peroxide such as hydrogen peroxide
• a strong alkali base preferably a hydroxide base such as sodium hydroxide
• a polar organic solvent preferably an ether such as tetrahydrofuran
• Step E involves the iodination of an alcohol of formula 5 to obtain an iodide of formula 6.
• the iodination is conducted in the presence of: 1) an iodinating reagent such l 2 ; 2) a phosphorus-containing compound such as triphenylphoshine; 3) a weak base, preferably a weak nitrogen-containing base such as imidazole; and 4) a polar organic solvent, preferably an ester such as ethyl acetate, at a temperature of between -10°C and 40°C, preferably at 25°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• an iodinating reagent such l 2
• a phosphorus-containing compound such as triphenylphoshine
• 3) a weak base preferably a weak nitrogen-containing base such as imidazole
• a polar organic solvent preferably an ester such as ethyl acetate
• Step F involves the two stage iodination of an alkene of formula X to obtain an iodide of formula 6.
• the first stage of the iodination is conducted in the presence of: 1 ) a borane such as 9-borabicyclo[3.3.1]nonane and 2) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -10°C and 40°C, preferably at 0°C, for a period of between 1 hour and 48 hours, preferably for 24 hours.
• a borane such as 9-borabicyclo[3.3.1]nonane
• a polar organic solvent preferably an ether such as tetrahydrofuran
• the second stage of the iodination is conducted in the presence of l 2 ; and 2) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -10°C and 40°C, preferably at 0°C, for a period of between 10 minutes and 8 hours.
• a polar organic solvent preferably an ether such as tetrahydrofuran
• Step G involves the phoshine addition reaction of an iodide of formula 6 to obtain a phosphonium iodide salt of formula 7.
• the phoshine addition reaction is conducted in the presence of: 1 ) a phosphorus reagent such as triphenylphosphine; 2) a base, preferably an amine base such as diisopropylethylamine; and 3) an organic solvent, preferably a polar aprotic solvent such as acetonitrile, at a temperature of between 25°C and 150°C, preferably at 90°C, for a period of between 1 hour and 72 hours, preferably for 18 hours.
• a phosphorus reagent such as triphenylphosphine
• a base preferably an amine base such as diisopropylethylamine
• an organic solvent preferably a polar aprotic solvent such as acetonitrile
• Step A involves the acylation of a phosphonate of formula 1 with an acid chloride of formula 2 to obtain a ketophosphonate of formula 3.
• the acylation is conducted in the presence of: 1) a strong base, preferably an amine salt, more preferably a disubstituted amine salt such as lithiumdiisopropylamide or lithiumhexamethyldisilazide; and 2) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -100°C and 0°C, preferably from -100°C to -40°C, for a period of between 10 minutes and 8 hours, preferably for 2 hours.
• a strong base preferably an amine salt, more preferably a disubstituted amine salt such as lithiumdiisopropylamide or lithiumhexamethyldisilazide
• a polar organic solvent preferably an ether such as tetrahydrofuran
• Step B involves the acylation of a phosphonate of formula 1 with an amide of formula 4 to obtain a ketophosphonate of formula 3.
• the acylation is conducted in the presence of: 1) a strong base, preferably an amine salt, more preferably a disubstituted amine salt such as lithiumdiisopropylamide or lithiumhexamethyldisilazide; and 2) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -100°C and 20°C, preferably from -78°C to 0°C, for a period of between 10 minutes and 8 hours, preferably for 2 hours.
• a strong base preferably an amine salt, more preferably a disubstituted amine salt such as lithiumdiisopropylamide or lithiumhexamethyldisilazide
• a polar organic solvent preferably an ether such as tetrahydrofuran
• Step A involves the alkylation of an alcohol of formula J. to obtain an ether of formula 2.
• the alkylation is conducted in the presence of: 1) a reactive benzylating reagent, preferably a reactive para-methoxybenzylating reagent such as p-methoxybenzyl-2,2,2-trichloroacetimidate; 2) a proton source, preferably a sulfonic acid such as pyridinium p-toluenesulfonate; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -78°C and 25°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a reactive benzylating reagent preferably a reactive para-methoxybenzylating reagent such as p-methoxybenzyl-2,2,2-trichloroacetimidate
• Step B involves the reduction of an ether of formula 2 to obtain an alcohol of formula 3.
• the reduction is conducted in the presence of: 1) a metal hydride, preferably an aluminum hydride such as lithium aluminum hydride or diisobutylaluminum hydride; and 2) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -100°C and 10°C, preferably from -78°C to 0°C, for a period of between 10 minutes and 8 hours, preferably for 2 hours.
• a metal hydride preferably an aluminum hydride such as lithium aluminum hydride or diisobutylaluminum hydride
• a polar organic solvent preferably an ether such as tetrahydrofuran
• Step C involves the alkylation of an alcohol of formula 3 to obtain an ether of formula 4.
• the alkylation is conducted in the presence of: 1) an alcohol of formula A * OH, where A * is as described above; 2) a coupling reagent such as diethyl azodicarboxylate; 3) a phosphine such as triphenylphosphine; and 4) a polar organic solvent, such tetrahydrofuran, at a temperature of between -78°C and 60°C, preferably between -20°C and 40°C, for a period of between 2 and 72 hours, preferably for 16 hours.
• Step D involves the oxidative hydrolysis of an ether of formula 4 to an alcohol of formula 5.
• the oxidative hydrolysis is conducted in the presence of: 1 ) an oxidant, preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone; 2) water; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 1 hour and 72 hours, preferably for 1 hour.
• an oxidant preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone
• water preferably a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 1 hour and 72 hours
• Step E involves the oxidation of an alcohol of formula 5 to obtain an aldehyde of formula 6.
• the oxidation is conducted in the presence of: 1 ) an oxidizing reagent, preferably a mild oxidizing reagent such as the combinations of oxalyl chloride, DMSO and triethylamine; sulfur trioxide-pyridine complex, DMSO and triethylamine; and 2,2,6,6-tetramethyl-1- piperidinyloxy free radical and diacetoxyiodobenzene; and 2) an inert organic solvent, preferably a polar organic solvent such as methylene chloride, at a temperature of between -78°C and 40°C, preferably from -20°C to 25°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• an oxidizing reagent preferably a mild oxidizing reagent such as the combinations of oxalyl chloride, DMSO and triethylamine; sulfur
• Step A involves the palladium-mediated coupling of an alkyl zinc bromide of formula 1 and a vinyl iodide of formula 2 to obtain an alkene of formula 3.
• the palladium-mediated coupling is conducted in the presence of: 1) a palladium reagent such as tetrakis(triphenylphosphine)palladium(0); and 2) a polar organic solvent, preferably an ether such as diethyl ether or tetrahydrofuran, at a temperature of between -78°C and 25°C, for a period of between 1 hour and 72 hours.
• a palladium reagent such as tetrakis(triphenylphosphine)palladium(0)
• a polar organic solvent preferably an ether such as diethyl ether or tetrahydrofuran
• Step B involves the amidation of an alkene of formula 3 to obtain an amide of formula 4.
• the amidation is conducted in the presence of: 1 ) an O, N-dialkylated hydroxylamine such as N,N-dimethylhydroxylamine hydrochloride; 2) an organometallic reagent, preferably an alkylmagnesium halide or a trialkylaluminum reagent such as trimethylaluminum; and 3) an organic solvent, preferably a hydrocarbon such as toluene or hexane, or a mixture of the two, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 1 hour and 72 hours, preferably for 1 hour.
• an O, N-dialkylated hydroxylamine such as N,N-dimethylhydroxylamine hydrochloride
• an organometallic reagent preferably an alkylmagnesium halide or a trialkylaluminum reagent such as trimethyl
• Step C involves the addition reaction of an amide of formula 4 with a metalloalkane, preferably an alkyllithium or alkylmagnesium halide reagent such as ethylmagnesium bromide, to obtain a ketone of formula 5.
• a metalloalkane preferably an alkyllithium or alkylmagnesium halide reagent such as ethylmagnesium bromide
• the addition reaction is conducted in the presence of a polar organic solvent such as tetrahydrofuran, at temperature of between -100°C and 0°C, preferably at -78°C, for a period of between 1 hour and 72 hours, preferably for 4 hours.
• Step D involves the addition reaction of a ketone of formula 5 with an aldehyde of formula E * CHO to obtain a hydroxyketone of formula 6.
• the addition reaction is conducted in: 1 ) the presence a Lewis acid, preferably a boron or titanium reagent such as trisopropoxytitanium chloride; and 2) a polar organic solvent, preferably an ether such as diethyl ether or tetrahydrofuran, at a temperature of between -100°C and 0°C, preferably at -78°C, for a period of between 1 hour and 72 hours, preferably for 16 hours.
• a Lewis acid preferably a boron or titanium reagent such as trisopropoxytitanium chloride
• a polar organic solvent preferably an ether such as diethyl ether or tetrahydrofuran
• Step E involves the alkylation of a hydroxyketone of formula 6 to obtain an ether of formula 7.
• the alkylation is conducted in the presence of: 1 ) a reactive benzylating reagent, preferably a reactive para-methoxybenzylating reagent such as p-methoxybenzyl-2,2,2- trichloroacetimidate; 2) a proton source, preferably a sulfonic acid such as pyridinium p-toluenesulfonate; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -78°C and 25°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a reactive benzylating reagent preferably a reactive para-methoxybenzylating reagent such as p-methoxybenzyl-2,2,2- trichloroace
• Step F involves the reduction of an ether of formula 7 to obtain an alcohol of formula 8.
• the reduction is conducted in the presence of: 1) a reducing agent, preferably an aluminum hydride or borohydride, such as lithium tri-t-butoxyaluminum hydride; 2) a polar organic solvent preferably an ether such as diethyl ether or tetrahydrofuran, at a temperature of between -100°C and 0°C, preferably at -78°C, for a period of between 1 hour and 72 hours, preferably for 16 hours.
• a reducing agent preferably an aluminum hydride or borohydride, such as lithium tri-t-butoxyaluminum hydride
• a polar organic solvent preferably an ether such as diethyl ether or tetrahydrofuran
• Step G involves the silylation of an alcohol of formula 8 to obtain an ether of formula 9.
• the silylation is conducted in the presence of: 1) a silylating reagent, preferably a t-butyldimethylsilylating reagent such as t-butyldimethylsilyltriflate; 2) a weak base, preferably a nitrogen-containing base, more preferably a pyridine base such as 2,6-lutidine; and 3) an inert organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -100°C and 5°C, preferably at -20°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• a silylating reagent preferably a t-butyldimethylsilylating reagent such as t-butyldimethylsilyltriflate
• a weak base preferably a nitrogen-containing base, more preferably a
• Step A concerns the carbamoylation of the olefin of formula 1 with a an isocyanate either of formula F * NCO or CI 3 C(O)NCO to give a carbamate of formula 2.
• the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• a protic organic solvent preferably an alcohol such as methanol
• a base for example, a carbonate such as potassium carbonate
• Step B involves the reduction of a carbamate of formula 2 to obtain an alcohol of formula 3.
• the reduction is conducted in the presence of: 1) a reducing agent, preferably an aluminum hydride or borohydride, such as lithium tri-t-butoxyaluminum hydride; and 2) a polar organic solvent preferably an ether such as diethyl ether or tetrahydrofuran, at a temperature of between -100°C and 0°C, preferably at -78°C, for a period of between 1 hour and 72 hours, preferably for 16 hours.
• a reducing agent preferably an aluminum hydride or borohydride, such as lithium tri-t-butoxyaluminum hydride
• a polar organic solvent preferably an ether such as diethyl ether or tetrahydrofuran
• Step C involves the silylation of an alcohol of formula 3 to obtain an ether of formula 4.
• the silylation is conducted in the presence of: 1) a silylating reagent, preferably a t-butyldimethylsilylating reagent such as t-butyldimethylsilyltriflate; 2) a weak base, preferably a nitrogen-containing base, more preferably a pyridine base such as 2,6-lutidine; and 3) an inert organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -100°C and 5°C, preferably at -20°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• a silylating reagent preferably a t-butyldimethylsilylating reagent such as t-butyldimethylsilyltriflate
• a weak base preferably a nitrogen-containing base, more preferably a
• Step A concerns the silylation of an alcohol of formula 1 to obtain an ether of formula 2.
• the silylation is conducted in the presence of: 1 ) a silylating reagent, preferably a t-butyldimethylsilylating reagent such as t- butyldimethylsilyltriflate; 2) a weak base, preferably a nitrogen-containing base, more preferably a pyridine base such as 2,6-lutidine; and 3) an inert organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -100°C and 5°C, preferably at -20°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• a silylating reagent preferably a t-butyldimethylsilylating reagent such as t- butyldimethylsilyltriflate
• a weak base preferably a nitrogen-containing base, more preferably
• Step B concerns the carbamoylation of the ether of formula 2 with a an isocyanate either of formula F * NCO or CI 3 C(O)NCO to give a carbamate of formula 3.
• the carbamoylation is conducted in the presence of a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine, in a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably between 0°C and 50°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 24 hours.
• a Lewis acid such as Bu 2 Sn(OAc) 2 or weak base such as triethylamine
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated solvent such as methylene chloride at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, in the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated solvent such as methylene chloride
• a protic organic solvent preferably an alcohol such as methanol
• a base for example, a carbonate such as potassium carbonate
• Step C concerns the hydrolysis of a carbamate of formula 3 to a substituted polyketide of formula 4.
• the hydrolysis reaction is conducted in the presence of: 1 ) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of between 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
• Step A involves the addition reaction of an alkene of formula 1 to obtain a ketone of formula 2.
• the addition is conducted in the presence of:
• an O,N-dialkylated hydroxylamine such as N,N-dimethylhydroxylamine hydrochloride
• Step B involves the addition reaction of a ketone of formula 2 with methacrolein to obtain a hydroxyketone of formula 3.
• the addition reaction is conducted in: 1 ) the presence of a Lewis acid, preferably a tin reagent such as tin(ll) triflate; and 2) a polar organic solvent, preferably an ether such as diethyl ether or tetrahydrofuran, at a temperature of between - 100°C and 0°C, preferably at -78°C, for a period of between 1 hour and 72 hours, preferably for 16 hours.
• a Lewis acid preferably a tin reagent such as tin(ll) triflate
• a polar organic solvent preferably an ether such as diethyl ether or tetrahydrofuran
• Step C involves the reduction of a hydroxyketone of formula 3 to obtain an alcohol of formula 4.
• the reduction is conducted in the presence of: 1 ) a reducing agent, preferably an aluminum hydride, such as diisobutylaluminum hydride; and 2) a polar organic solvent, preferably an ether such as diethyl ether or tetrahydrofuran, at a temperature of between -100°C and 0°C, preferably at -78°C, for a period of between 1 hour and 72 hours, preferably for 16 hours.
• a reducing agent preferably an aluminum hydride, such as diisobutylaluminum hydride
• a polar organic solvent preferably an ether such as diethyl ether or tetrahydrofuran
• Step D involves the oxidation of an alcohol of formula 4 to obtain a cyclic ether of formula 5.
• the oxidation is conducted in the presence of: 1 ) an oxidant, preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone; and 2) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -40°C and 20°C, preferably at 0°C, for a period of between 1 hour and 72 hours, preferably for 16 hours.
• an oxidant preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone
• a polar organic solvent preferably a halogenated hydrocarbon such as methylene chloride
• Step E involves the silylation of an alcohol of formula 5 to obtain a silyl ether of formula 6.
• the silylation is conducted in the presence of: 1 ) a silylating reagent, preferably a triethylsilylating reagent such as triethylsilyl triflate; 2) a weak base, preferably a nitrogen- containing base, more preferably a pyridine base such as 2,6-lutidine; and 3) an inert organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -100°C and 5°C, preferably at -20°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• a silylating reagent preferably a triethylsilylating reagent such as triethylsilyl triflate
• a weak base preferably a nitrogen- containing base, more preferably a pyridine base such as 2,6
• Step F involves the two stage hydroxylation of a silyl ether of formula 6 to obtain an alcohol of formula 7.
• the first stage of the hydroxylation is conducted in the presence of: 1) a borane such as 9-borabicyclo[3.3.1]nonane; and 2) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -10°C and 40°C, preferably at 0°C, for a period of between 1 hour and 48 hours, preferably for 24 hours.
• a borane such as 9-borabicyclo[3.3.1]nonane
• a polar organic solvent preferably an ether such as tetrahydrofuran
• the second stage of the hydroxylation is conducted in the presence of: 1) an oxidant, preferably a peroxide such as hydrogen peroxide; 2) a strong alkali base, preferably a hydroxide base such as sodium hydroxide; and 3) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -10°C and 40°C, preferably at 0°C, for a period of between 10 minutes and 8 hours, preferably for 1 hour.
• an oxidant preferably a peroxide such as hydrogen peroxide
• a strong alkali base preferably a hydroxide base such as sodium hydroxide
• a polar organic solvent preferably an ether such as tetrahydrofuran
• Step G involves the oxidation of an alcohol of formula 7 to obtain an aldehyde of formula 8.
• the oxidation is conducted in the presence of: 1 ) an oxidizing reagent, preferably a mild oxidizing reagent such as the combinations of oxalyl chloride, DMSO and triethylamine; sulfur trioxide-pyridine complex, DMSO and triethylamine; and 2,2,6,6-tetramethyl-1 - piperidinyloxy free radical and diacetoxyiodobenzene; and 2) an inert organic solvent, preferably a polar organic solvent such as methylene chloride, at a temperature of between -78°C and 40°C, preferably from -20°C to 25°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• an oxidizing reagent preferably a mild oxidizing reagent such as the combinations of oxalyl chloride, DMSO and triethylamine;
• Step H involves the olefination of an aldehyde of formula 8 to obtain a diene of formula 9.
• the olefination is conducted in the presence of: 1 ) a halogenated silyl propene such as 1-bromo-1-trimethylsilyl-2-propene; 2) a chromium(ll) reagent such as chromium(ll)chloride; and 3) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -100°C and 40°C, preferably at 20°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a halogenated silyl propene such as 1-bromo-1-trimethylsilyl-2-propene
• a chromium(ll) reagent such as chromium(ll)chloride
• 3) a polar organic solvent preferably an ether such as tetrahydro
• Step I involves the reductive hydrolysis of a diene of formula 9 to obtain an alcohol of formula 10.
• the reductive hydrolysis is conducted in the presence of: 1) a Lewis acidic hydride, preferably an aluminum hydride such as diisobutylaluminum hydride; and 2) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -100°C and 5°C, preferably at -78°C, for a period of between 10 minutes and 48 hours, preferably for 1 hour.
• a Lewis acidic hydride preferably an aluminum hydride such as diisobutylaluminum hydride
• a polar organic solvent preferably a halogenated hydrocarbon such as methylene chloride
• Step J involves the iodination of an alcohol of formula 10 to obtain an iodide of formula 11.
• the iodination is conducted in the presence of: 1 ) an iodinating reagent such as iodine; 2) a phosphorus-containing compound such as triphenylphoshine; 3) a weak base, preferably a weak nitrogen-containing base such as imidazole; and 4) a polar organic solvent, preferably an ester such as ethyl acetate, at a temperature of between -10°C and 40°C, preferably at 25°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• Scheme 28
• Step A involves the palladium-mediated coupling of a vinyl iodide of formula and an alkyl iodide of formula 2 to obtain an alkene of formula 3.
• the palladium-mediated coupling is conducted in the presence of: 1) a hindered organometallic reagent, preferably a hindered organolithium reagent such as t-butyllithium; 2) either a zinc halide such as zinc chloride or a hindered boron reagent such as 9-methoxy- 9-borabicyclo[3.3.1]nonane; 3) a palladium reagent such as tetrakis(triphenylphosphine)- palladium(O) or [1 ,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(ll); and 4) a polar organic solvent, preferably an ether such as diethyl ether, at a temperature of between
• Step B concerns the hydrolysis of an alkene 3 to an alcohol of formula 4.
• the hydrolysis reaction is conducted in the presence of: 1 ) a protic acid, preferably an aqueous protic acid solution, more preferably an aqueous hydrogen halide solution such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, more preferably a mixture of an aliphatic alcohol and an ether such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of between 5 minutes and 24 hours, preferably between 0.5 and 12 hours.
• a protic acid preferably an aqueous protic acid solution, more preferably an aqueous hydrogen halide solution such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents, more preferably a mixture of an aliphatic alcohol and an ether such
• Step C concerns the carbamoylation of an alcohol of formula 4 with an isocyanate of formula CI 3 C(O)NCO to give a carbamate of formula 5.
• the carbamoylation is conducted in the presence of a polar aprotic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -20°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours; the work-up of this step is conducted in the presence of a protic organic solvent, preferably an alcohol such as methanol, and the presence of a base, for example, a carbonate such as potassium carbonate, at a temperature of between 0°C and 100°C, preferably at 25°C, for a period of between 5 minutes and 72 hours, preferably between 1 hour and 8 hours.
• a polar aprotic solvent preferably a halogenated hydrocarbon such as methylene chloride
• Step D involves the oxidative hydrolysis of a carbamate of formula 5 to a substituted polyketide of formula 6.
• the oxidative hydrolysis is conducted in the presence of: 1 ) an oxidant, preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone; 2) water; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 1 hour and 72 hours, preferably for 1 hour.
• an oxidant preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone
• water preferably a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period
• the present invention pertains inter alia to a process for the preparation of a compound of formula Id
• A has the meaning as defined above for a compound of formula I, or an acid or base addition salt thereof, where possible, characterized in that a iodide of formula II wherein PMB stands for p-methoxybenzyl and TES means triethylsilyl, is reacted in a first step in a Pd-mediated coupling reaction with a vinyl iodide of formula (III)
• Step A involves the reduction of an imide of formula X to obtain an alcohol of formula 2.
• the reduction is conducted in the presence of: 1 ) a hydride reducing agent such as lithium borohydride; 2) a protic organic solvent, preferably a lower alkanol such as ethanol; and 3) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably at 25°C, for a period of between 10 minutes and 48 hours, preferably for 18 hours.
• Step B involves the oxidation of an alcohol of formula 2 to obtain a cyclic ether of formula 3.
• the oxidation is conducted in the presence of: 1) an oxidant, preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone; and 2) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -40°C and 20°C, preferably at 0°C, for a period of between 1 hour and 72 hours, preferably for 16 hours.
• an oxidant preferably a quinone such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone
• a polar organic solvent preferably a halogenated hydrocarbon such as methylene chloride
• Step C involves the two stage hydroxylation of a cyclic ether of formula 3 to obtain an alcohol of formula 4.
• the first stage of the hydroxylation is conducted in the presence of: 1) a borane such as 9-borabicyclo[3.3.1]nonane; and 2) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -10°C and 40°C, preferably at 0°C, for a period of between 1 hour and 48 hours, preferably for 24 hours.
• a borane such as 9-borabicyclo[3.3.1]nonane
• a polar organic solvent preferably an ether such as tetrahydrofuran
• the second stage of the hydroxylation is conducted in the presence of: 1) an oxidant, preferably a peroxide such as hydrogen peroxide; 2) a strong alkali base, preferably a hydroxide base such as sodium hydroxide; and 3) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -10°C and 40°C, preferably at 0°C, for a period of between 10 minutes and 8 hours, preferably for 1 hour.
• an oxidant preferably a peroxide such as hydrogen peroxide
• a strong alkali base preferably a hydroxide base such as sodium hydroxide
• a polar organic solvent preferably an ether such as tetrahydrofuran
• Step D involves the iodination of an alcohol of formula 4 to obtain an iodide of formula 5.
• the iodination is conducted in the presence of: 1) an iodinating reagent such as iodine; 2) a phosphorus-containing compound such as triphenylphoshine; 3) a weak base, preferably a weak nitrogen-containing base such as imidazole; and 4) a polar organic solvent, preferably an ester such as ethyl acetate, at a temperature of between -10°C and 40°C, preferably at 25°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• an iodinating reagent such as iodine
• a phosphorus-containing compound such as triphenylphoshine
• 3) a weak base preferably a weak nitrogen-containing base such as imidazole
• a polar organic solvent preferably an ester such as ethyl acetate
• Step E involves the phoshine addition reaction of an iodide of formula 5 to obtain a phosphonium iodide salt of formula 6.
• the phoshine addition reaction is conducted in the presence of: 1) a phosphorus reagent such as triphenylphosphine; 2) a base, preferably an amine base such as diisopropylethylamine; and 3) an organic solvent, preferably a polar aprotic solvent such as acetonitrile, at a temperature of between 25°C and 150°C, preferably at 90°C, for a period of between 1 hour and 72 hours, preferably for 18 hours.
• a phosphorus reagent such as triphenylphosphine
• a base preferably an amine base such as diisopropylethylamine
• an organic solvent preferably a polar aprotic solvent such as acetonitrile
• Step F involves the olefination of an aldehyde of formula 7 with a phosphonium iodide salt of formula 6 to obtain an alkene of formula 8.
• the olefination is conducted in the presence of: 1 ) a strong base, preferably an alkali metal salt such as potassium hexamethyldisilazide or butyllithium; and 2) an inert organic solvent, preferably a hydrocarbon such as toluene, or an ether such as tetrahydrofuran, at a temperature of between -78°C and 25°C, preferably at 0 C C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a strong base preferably an alkali metal salt such as potassium hexamethyldisilazide or butyllithium
• an inert organic solvent preferably a hydrocarbon such as toluene, or an ether such as tetrahydrofuran
• Step G involves the reductive hydrolysis of an alkene of formula 8 to obtain an alcohol of formula 9.
• the reductive hydrolysis is conducted in the presence of: 1) a Lewis acidic hydride, preferably an aluminum hydride such as diisobutylaluminum hydride; and 2) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -100°C and 5°C, preferably at -78°C, for a period of between 10 minutes and 48 hours, preferably for 1 hour.
• a Lewis acidic hydride preferably an aluminum hydride such as diisobutylaluminum hydride
• a polar organic solvent preferably a halogenated hydrocarbon such as methylene chloride
• Step H involves the oxidation of an alcohol of formula 9 to obtain an aldehyde of formula 10.
• the oxidation is conducted in the presence of: 1) an oxidizing reagent, preferably a mild oxidizing reagent such as the combinations of oxalyl chloride, DMSO and triethylamine; sulfur trioxide-pyridine complex, DMSO and triethylamine; and 2,2,6,6-tetramethyM- piperidinyloxy free radical and diacetoxyiodobenzene; and 2) an inert organic solvent, preferably a polar organic solvent such as methylene chloride, at a temperature of between -78°C and 40°C, preferably from -20°C to 25°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• an oxidizing reagent preferably a mild oxidizing reagent such as the combinations of oxalyl chloride, DMSO and triethylamine; sulfur
• Step I involves the olefination of an aldehyde of formula 10 to obtain an iodoalkene of formula JJ..
• the olefination is conducted in the presence of: 1 ) an alkyltriphenylphosphonium salt such as ethyltriphenylphosphonium iodide; 2) a strong base, preferably an alkali metal salt such as potassium hexamethyldisilazide or butyllithium; 3) an iodinating agent such as iodine; and 4) an inert organic solvent, preferably a hydrocarbon such as toluene, or an ether such as tetrahydrofuran, at a temperature of between -78°C and 25°C, preferably at -20°C, for a period of between 10 minutes and 48 hours, preferably for 1 hour.
• an alkyltriphenylphosphonium salt such as ethyltriphenylphosphonium iodide
• Step A involves the addition reaction of an aldehyde of formula 1 to obtain an alkyne of formula 2.
• the addition is conducted in the presence of: 1 ) a propargyl alcohol, mesylate salt such as 3-butyn-2-ol, methanesulfonate; 2) a palladium reagent such as [1 ,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(ll); 3) an indium reagent such as indium(l) iodide; and 4) polar organic mixture of solvents such as tetrahydrofuran and hexamethylphosphoramide, at a temperature of between -10°C and 20°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 2 hours.
• solvents such as tetrahydrofuran and hexamethylphosphoramide
• Step B involves the addition reaction of a alkyne of formula 2 to an aldehyde having formula ACH 2 CHO to obtain a propargyl alcohol of formula 3.
• the alkyne addition is conducted in the presence of: 1) a Lewis acid, preferably a zinc Lewis acid such as zinc triflate; 2) a hydroxylamine, preferably an ethanolamine such as N-methyl-ephedrine; 3) a base, preferably an amine base such as triethylamine; and 4) an inert organic solvent, preferably a hydrocarbon such as toluene, at a temperature of between 0°C and 50°C, preferably at 25°C, for a period of between 10 minutes and 48 hours, preferably for 1 hour.
• a Lewis acid preferably a zinc Lewis acid such as zinc triflate
• a hydroxylamine preferably an ethanolamine such as N-methyl-ephedrine
• 3) a base preferably an amine base such as triethylamine
• Step C involves the partial hydrogenation of a propargyl alcohol of formula 3 to obtain an alkene of formula 4.
• the hydrogenation is conducted in the presence of: 1 ) hydrogen; 2) a transition metal catalyst such as palladium; 3) an optional palladium poison such as quinoline; and 4) an organic solvent, preferably an alcohol such as methanol, or an ester such as ethyl acetate, at a temperature of between 0°C and 35°C, preferably at 25°C, for a period of between 1 minute and 12 hours, preferably for 30 minutes.
• Step D involves the alkylation of an alkene of formula 4 to obtain an ether of formula 5.
• the alkylation is conducted in the presence of: 1) a reactive benzylating reagent, preferably a reactive para-methoxybenzylating reagent such as p-methoxybenzyl-2,2,2-trichloro- acetimidate; 2) a proton source, preferably a sulfonic acid such as pyridinium p-toluene- sulfonate; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -78°C and 25°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a reactive benzylating reagent preferably a reactive para-methoxybenzylating reagent such as p-methoxybenzyl-2,2,2-trichloro- ace
• Step E concerns the hydrolysis of an ether of formula 5 to an alcohol of formula 6.
• the hydrolysis reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, more preferably a mixture of an aliphatic alcohol and an ether such as methanol and tetrahydrofuran, at a temperature of between -20°C and 40°C, preferably between 20°C and 25°C, for a period of between 5 minutes and 24 hours, preferably between 0.5 and 12 hours.
• a protic acid preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution such as aqueous hydrogen chloride
• a polar organic solvent preferably a mixture of polar organic solvents, more preferably a mixture of an aliphatic alcohol and an ether such as m
• Step F involves the oxidation of an alcohol of formula 6 to obtain an aldehyde of formula 7.
• the oxidation is conducted in the presence of: 1) an oxidizing reagent, preferably a mild oxidizing reagent such as the combinations of oxalyl chloride, DMSO and triethylamine; sulfur trioxide-pyridine complex, DMSO and triethylamine; and 2,2,6,6-tetramethyl-1- piperidinyloxy free radical and diacetoxyiodobenzene; and 2) an inert organic solvent, preferably a polar organic solvent such as methylene chloride, at a temperature of between -78°C and 40°C, preferably from -20°C to 25°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• an oxidizing reagent preferably a mild oxidizing reagent such as the combinations of oxalyl chloride, DMSO and triethylamine; sulfur trioxid
• Step G involves the olefination of an aldehyde of formula 7 to obtain an iodoalkene of formula 8.
• the olefination is conducted in the presence of: 1) an alkyltriphenylphosphonium salt such as ethyltriphenylphosphonium iodide; 2) a strong base, preferably an alkali metal salt such as potassium hexamethyldisilazide or butyllithium; 3) an iodinating agent such as iodine; and 4) an inert organic solvent, preferably a hydrocarbon such as toluene, or an ether such as tetrahydrofuran, at a temperature of between -78°C and 25°C, preferably at -20°C, for a period of between 10 minutes and 48 hours, preferably for 1 hour.
• an alkyltriphenylphosphonium salt such as ethyltriphenylphosphonium iodide
• Step A involves the amidation of a carboxylic acid of formula 1. to obtain an amide of formula 2.
• the amidation is conducted in the presence of: 1) an O,N-dialkylated hydroxylamine such as N,N-dimethylhydroxylamine hydrochloride; 2) a carboxylic acid coupling reagent, preferably a diimide such as 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride, and a suitable activating agent common to diimide coupling reactions, such as 1 -hydroxybenzotriazole; and 3) a polar organic solvent, preferably a low molcular weight amide such as DMF, at a temperature of between 0°C and 40°C, preferably at 25°C, for a period of between 1 and 24 hours.
• an O,N-dialkylated hydroxylamine such as N,N-dimethylhydroxylamine hydrochloride
• a carboxylic acid coupling reagent preferably
• Step B involves the alkylation of an amide of formula 2 to obtain an ether of formula 3.
• the alkylation is conducted in the presence of: 1) a reactive benzylating reagent, preferably a reactive para-methoxybenzylating reagent such as p-methoxybenzyl-2,2,2-trichloro- acetimidate; 2) a proton source, preferably a sulfonic acid such as pyridinium p-toluene- sulfonate; and 3) a polar organic solvent, preferably a halogenated hydrocarbon such as methylene chloride, at a temperature of between -78°C and 25°C, preferably at 0°C, for a period of between 10 minutes and 48 hours, preferably for 3 hours.
• a reactive benzylating reagent preferably a reactive para-methoxybenzylating reagent such as p-methoxybenzyl-2,2,2-trichloro- acet
• Step C involves the reduction of an ether of formula 3 to obtain an aldehyde of formula 4.
• the reduction is conducted in the presence of: 1) a metal hydride, preferably an aluminum hydride such as diisobutylaluminum hydride; and 2) a polar organic solvent, preferably an ether such as tetrahydrofuran, at a temperature of between -100°C and 10°C, preferably from -78°C to 0°C, for a period of between 10 minutes and 8 hours, preferably for 2 hours.
• a metal hydride preferably an aluminum hydride such as diisobutylaluminum hydride
• a polar organic solvent preferably an ether such as tetrahydrofuran
• the product of each reaction described above may, if desired, be purified by conventional techniques such as chromatography or recrystallization (if a solid), the crude product of one reaction is advantageously employed in the following reaction without purification.
• ADGMA Anchorage Dependent Growth Monolayer Assay
• MIP 101 colon carcinoma a cell line representative for the important tumor types, viz., MIP 101 colon carcinoma, HCT 116 colon carcinoma, 1 A9 ovarian carcinoma and 1A9PTX22 ovarian carcinoma were utilized; and 2) a tetrazolium derivative, viz., MTT, was utilized to determine cell density.
• MTT a tetrazolium derivative
• the ADGMA compares the number of viable cells following a 3-day exposure to a test compound relative to the number of cells present at the time the test compound was added.
• Cell viability is measured using a tetrazolium derivative, viz., 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyl-tetrazolium bromide (MTT) that is metabolically reduced in the presence of an electron coupling agent (PMS; phenazine methosulfate) by viable cells to a water-soluble formazan derivative.
• PMS electron coupling agent
• the absorbance at 540 nm ( A540) of the formazan derivative is proportional to the number of viable cells.
• the IC 50 for a test compound is the concentration of compound required to reduce the final cell number to 50% of the final control cell number. If cell proliferation is inhibited, the assay further defines compounds as cytostatic (cell number after 3-day compound incubation >cell number at time of compound addition) or cytotoxic (cell number after 3-day compound incubation ⁇ cell number at time of compound addition).
• the HCT 116 colon carcinoma cell line was obtained from the American Type Culture Collection (ATCC, Rockville, MD).
• the MIP 101 colon carcinoma was obtained from Dr. Robert Kramer (Bristol Meyers Squibb) and was previously described (Niles RM, Wilhelm SA, Steele GD JR, Burke B, Christensen T, Dexter D, O'Brien MJ, Thomas P, Zamcheck N. Isolation and characterization of an undifferentiated human colon carcinoma cell line (MIP 101). Cancer Invest. 1987;5(6):545-52.).
• the 1A9 and the 1A9PTX22 ovarian tumor cell lines were obtained from Dr.
• the 1A9 is a clone of the ovarian carcinoma cell line, A2780 (Giannakakou P, Sackett, DL, .Kang Y-K, Zhan Z, ButersJTM, Fojo T, Poruchynsky MS. Paclitaxel-resistant human ovarian cancer cells have mutant ⁇ -tubulins that impaired paclitaxel-driven polymerization. J. Biol. Chem. 1997, 272(4):17118-17125).
• the 1A9PTX22 subline was isolated as an individual clone from the 1A9 cell line in a single step selection by exposure to 5 ng/mL paclitaxel in the presence of 5 ⁇ g/mL of verapamil. All cell lines were used between passages 4-20 following thawing. MIP 101 colon carcinoma, HCT 116 colon carcinoma, 1A9 ovarian carcinoma and 1A9PTX22 ovarian carcinoma cell lines are maintained and plated in RPM1 1640 medium containing 10% fetal bovine serum..
• Cells are trypsinized and counted using a hemacytometer to determine cell concentrations. Cells were then plated in their respective maintenance media (200 ⁇ L/well) in 96-well plates at the following concentrations: MIP 101 , 2000 cells/well, HCT 116, 2000 cells/well, 1A9, 10000 cells/well, and 1A9PTX22, 10000 cells/well. The number of cells/well was determined in preliminary experiments, and resulted in 75-90% of confluency by day 4 after plating. Initial cell densities, assayed one day after plating, are roughly 0.10-0.20 A540 absorbance units greater than the media blank. Ninety-six-well plates were seeded on day 0 and the test compounds are added on day 1.
• a "time 0" plate was created that received media only in row A and one cell line/row in rows B-E.
• the "time 0" plate was processed 24 hours after plating (at the time when drugs were added to experimental plates), as follows: To each well 5 micoliters of the MTT stock solution (0.5 mg/mL in PBS) was added to each well and then incubated for three hours at 37°C, 5% CO2, in a humidified environment. Media was then carefully and completely removed. Plates were allowed to dry in the dark. Dimethylsulfoxide (DMSO) was added to each well (100 ⁇ L/well) and plates were placed on an orbital shaker for 2 hours.
• DMSO Dimethylsulfoxide
• a preferred intravenous single dosage per 3-6 week treatment cycle is 1-75 mg/kg body weight or, for most larger primates, a daily dosage of 50-1500 mg.
• a typical intravenous dosage is 45 mg/kg, once every three weeks.
• a small dose is administered initially and the dosage is gradually increased until the optimal dosage for the host under treatment is determined.
• the upper limit of dosage is that imposed by side effects and can be determined by trial for the host being treated.
• the compounds of formula I may be combined with one or more pharmaceutically acceptable carriers and, optionally, one or more other conventional pharmaceutical adjuvants and administered enterally, e.g., orally, in the form of tablets, capsules, caplets, etc. or parenterally, e.g., intraperitoneally or intravenously, in the form of sterile injectable solutions or suspensions.
• enteral and parenteral compositions may be prepared by conventional means.
• the compounds of formula I may be formulated into enteral and parenteral pharmaceutical compositions containing an amount of the active substance that is effective for inhibiting tumors, such compositions in unit dosage form and such compositions comprising a pharmaceutically acceptable carrier.
• the compounds according to the invention can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic agents.
• a compound of formula I can be administered for example in the case of tumour therapy in combination with chemotherapy, radiotherapy, immunotherapy, surgical intervention, or a combination of these.
• Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above.
• Other possible treatments are therapy to maintain the patient's status after tumour regression, or even chemopreventive therapy, for example in patients at risk.
• Therapeutic agents for possible combination are especially one or more antiproliferative, cytostatic or cytotoxic compounds, for example a chemotherapeutic agent or several agents selected from the group which includes, but is not limited to, an inhibitor of polyamine biosynthesis, an inhibitor of a protein kinase, especially of a serine/threonine protein kinase, such as protein kinase C, or of a tyrosine protein kinase, such as the EGF receptor tyrosine kinase, e.g. PKI166, the VEGF receptor tyrosine kinase, e.g. PTK787, or the PDGF receptor tyrosine kinase, e.g.
• a chemotherapeutic agent for example a chemotherapeutic agent or several agents selected from the group which includes, but is not limited to, an inhibitor of polyamine biosynthesis, an inhibitor of a protein kinase, especially of a serine/thre
• STI571 a cytokine, a negative growth regulator, such as TGF- ⁇ or IFN- ⁇ , an aromatase inhibitor, e.g. letrozole or anastrozole, an inhibitor of the interaction of an SH2 domain with a phosphorylated protein, antiestrogens, topoisomerase I inhibitors, such as irinotecan, topoisomerase II inhibitors, microtubule active agents, e.g.
• paclitaxel paclitaxel, discodermolide or an epothilone, alkylating agents, antineoplastic antimetabolites, such as gemcitabine or capecitabine, platin compounds, such as carboplatin or cisplatin, anti- angiogenic compounds, gonadorelin agonists, anti-androgens, bisphosphonates, e.g. AREDIA® or ZOMETA®, and trastuzumab.
• the structure of the active agents identified by code nos., generic or trade names may be taken from the actual edition of the standard compendium 'The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference.
• the present invention relates to the use of the compounds described herein and their pharmaceutically acceptable acid or base addition salts, where possible, for use in a method for the treatment of the human or animal body or for the manufacture of a pharmaceutical preparation for the treatment of a tumor disease.
• EXAMPLE 1 6-[(2S,3Z,8Z,11 S,12fl,13S,14S,15S,16Z)-14-[(aminocarbonyl)oxy]-2,6,12- trihydroxy-5,7,9,11 ,13,15-hexamethyl-3,8, 16,18-nonadecatetraenyl]tetrahydro-(6fl)-2H- pyran-2-one
• the mixture is stirred at -29°C for 18 hours.
• the reaction is quenched with 1 mL of 0.5N aqueous sodium potassium tartrate and the mixture is allowed to warm slowly to ambient temperature.
• the mixture is diluted with CH 2 CI and washed with aqueous saturated NaHCO 3 .
• the aqueous layer is back extracted with CH 2 CI 2 four times.
• the combined organic layers are washed with brine, dried with Na 2 SO and concentrated in vacuo to give the crude product as a white solid; m/z (ESI+) 846 (100 (M+Na + )).
• EXAMPLE 2 (5Z,8S,9ft,10S,11 S,12S,13Z)-11-[(aminocarbonyl)oxy]-3,9-dihydroxy-2,4,6,8, 10,12-hexamethyl-5,13,15-hexadecatrienyl ester cyclohexylcarbamic acid.
• EXAMPLE 3 (2Z,7Z,10S,11 fl,12S,13S,14S,15Z)-4,6,8,10,12,14-hexamethyl-1-phenoxy- 2,7, 15,17-octadecatetraene-5, 11 ,13-triol-13-carbamate.
• EXAMPLE 4 (2Z,7Z,10S,11 fl,12S,13S,14S,15Z)-13-[(aminocarbonyl)oxy]-5,11-dihydroxy- ⁇ /,4,6,8,10,12,14-heptamethyl- ⁇ Aphenyl 2,7,15,17-octadecatetraenamide.
• THF THF (10 mL) solution of (2 ?,3fl,4S,5Z,8S,9f?,10R,11 S,12S,13Z)-3,9-bis[[(1 ,1-dimethylethyl) dimethylsilyl]oxy]-11 -hydroxy-2,4,6,8, 10,12-hexamethyl-5, 13,15-hexadecatrienal (300 mg, 0.505 mmol, 1 eq) at 23°C. After stirring for 20 minutes, NaBHAc 3 is added followed by addition of 1 drop of AcOH.
• EXAMPLE 6 Synthesis of (2S,3Z,5S,6S,7S,8Z,11 S,12f?,13fl,14S,15S,16Z)-1-cyclopentyl- 5,7,9, 11 , 13, 15-hexamethyl-3,8, 16, 18-nonadecatetraene-2,6, 12, 14-tetrol-14-carbamate.
• Hexamethyldisilazane 13.24 mL, 62.74 mmol, 2.3 eq
• n-BuLi 37.5 mL, 60 mmol, 1.6 M, 2.2 eq
• THF 50 mL
• the solution is warmed to 0°C and is stirred for 20 minutes.
• the solution is then cooled to -100°C and a pre-cooled (-78°C) THF (20 mL) solution of cyclopentylacetyl chloride (4 g, 27.28 mmol, 1 eq) and bis(2,2,2-trifluoroethyl)methylphosphonate (7.09 g, 27.28 mmol, 1 eq) is added dropwise over 10 minutes.
• the reaction mixture is stirred at -100°C an additional 20 minutes and stored overnight at -30°C.
• the cold reaction mixture is poured into a stirred mixture of 50 mL of 2N HCI and an equal volume of ice, and 100 mL of CH 2 CI 2 .
• EXAMPLE 7 Synthesis of (2S,3Z,5S,6S,7S,8Z,11 S,12r?,13f?,14S,15S,16Z)-1-isopropyl- 5,7,9,11 ,13,15-hexamethyl-3,8, 16, 18-nonadecatetraene-2,6, 12,14-tetrol-14-carbamate.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Hematology (AREA)
• Oncology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pyrane Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (4)

Applications Claiming Priority (10)

Publications (2)

Family

ID=27540954

Family Applications (1)

Country Status (7)

Families Citing this family (4)

Citations (2)

Family Cites Families (4)

• 2002
  • 2002-08-05 EP EP02794555A patent/EP1417195A1/en not_active Withdrawn
  • 2002-08-05 JP JP2003519052A patent/JP4243183B2/ja not_active Expired - Fee Related
  • 2002-08-05 BR BR0211762-2A patent/BR0211762A/pt not_active IP Right Cessation
  • 2002-08-05 US US10/212,535 patent/US6972292B2/en not_active Expired - Fee Related
  • 2002-08-05 WO PCT/EP2002/008734 patent/WO2003014102A1/en active Application Filing
  • 2002-08-05 CN CNB028154991A patent/CN100522956C/zh not_active Expired - Fee Related
  • 2002-08-05 CA CA002454081A patent/CA2454081A1/en not_active Abandoned
• 2004
  • 2004-09-28 US US10/951,857 patent/US7192980B2/en not_active Expired - Fee Related

Patent Citations (2)

Non-Patent Citations (3)

Also Published As

Similar Documents

Legal Events